Natural benzophenones are a class of compounds consisting of more than 300 members, which exhibit great structural diversity and bioactive properties. Many benzophenones have been reported from higher plants or fungi, most with polyisoprenylated benzophenone skeletons, and are mainly found in the Clusiaceae (formerly Guttiferae) family, a number from edible or medicinal species. Owing to their variable substituents and complex ring systems, many new polyisoprenylated benzophenones (PPBS), including ones with unusual skeletons, were isolated and identified. These natural benzophenones exhibit a range of biological activities including antifungal, anti-HIV, antimicrobial, antioxidant, antiviral and cytotoxic. Because of the increased numbers and biological importance of these unique natural product polyphenols, we will review natural benzophenones and provide an in-depth discussion of their structural diversity and biological activity. By focusing on these key developments in benzophenones, we will contribute a focused review, selecting examples mostly from the last 15 years, but extending our scope to other historically important benzophenones discovered prior to that time.